Abstract
Multifunctional N6-methyladenosine (m6A) has been revealed to be an important epigenetic component in various physiological and pathological processes, but its role in female ovarian aging remains unclear. Thus, we demonstrated m6A demethylase FTO downregulation and the ensuing increased m6A in granulosa cells (GCs) of human aged ovaries, while FTO-knockdown GCs showed faster aging-related phenotypes mediated. Using the m6A-RNA-sequence technique (m6A-seq), increased m6A was found in the FOS-mRNA-3′UTR, which is suggested to be an erasing target of FTO that slows the degradation of FOS-mRNA to upregulate FOS expression in GCs, eventually resulting in GC-mediated ovarian aging. FTO acts as a senescence-retarding protein via m6A, and FOS knockdown significantly alleviates the aging of FTO-knockdown GCs. Altogether, the abovementioned results indicate that FTO in GCs retards FOS-dependent ovarian aging, which is a potential diagnostic and therapeutic target against ovarian aging and age-related reproductive diseases.
Highlights
Driven by the postponement of pregnancy due to socioeconomic and demographic trends over the past several decades, female reproductive aging and ensuing age-related infertility have become increasingly prevalent [1, 2]
The abnormally increased mammalian N6methyladenosine (m6A) modification in Granulosa cells (GCs) of aged the figure, while FOS, NEDD9, and CDK6 were significantly ovaries was due to the downregulation of the demethylase different
The quantity of m6A was significantly higher in addition, RIP-qPCR was performed with an fat mass and obesity-associated protein (FTO) antibody and we the total RNA of GCs in aged ovaries than in normal ovaries found that the FTO protein could bind to FOS mRNA
Summary
Driven by the postponement of pregnancy due to socioeconomic and demographic trends over the past several decades, female reproductive aging and ensuing age-related infertility have become increasingly prevalent [1, 2]. GCs are one of the major participants in follicular initiation, recruitment, selection, dominance, ovulation, and luteinization, and they play an important role in early-onset ovarian dysfunction, polycystic ovarian syndrome, and some other pathological processes [9] They are decisive as to the fate of follicles and are signal transducers and responders to aging-related factors that affect follicles [10]. Previous studies indicated that it is of great significance to explore the epigenetic changes of GCs and the subsequent molecular biological mechanism behind them in the ovarian aging process [14, 15]. An increasing total m6A content was and mRNA-seq of FTO-knockdown COV434, which is shown in a revealed in GCs of aged ovaries, and changes in the expression Venn diagram (Fig. 2D).
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